Oral Cancers Without Known Risk Factors Show a Distinct Molecular Profile

Most head and neck cancers, particularly those arising in the oral cavity, have long been tied to a well-defined set of causes: tobacco, alcohol, and infection with oncogenic strains of Human papillomavirus. But a growing share of oral cavity squamous cell carcinoma (OCSCC) cases—especially among younger patients and women—appear in people without any of these exposures, and the biology of those tumors has remained unclear. 

A new study from researchers at the International Agency for Research on Cancer (IARC) and the Cancer Research Center of Lyon aims to fill that gap. The work, published in the International Journal of Oral Science, characterizes oral cancers in patients with "no identified risk factor"—termed NIRF OCSCC—and finds that the tumors form a molecularly distinct subtype shaped largely by internal cellular processes. 

"We aimed to uncover the molecular mechanisms driving these cancers and to determine whether they represent a distinct subtype with unique biological characteristics. Given that traditional carcinogenic exposures could not explain these cases, we sought to explore whether internal processes or alternative external influences might be responsible," said study lead Jiri Zavadil.

Using data from The Cancer Genome Atlas, the team analyzed 347 head and neck cancer samples—253 oral cavity cancers and 94 laryngeal cancers used as smoking-related controls. Multi-omics analysis examined DNA mutations, gene expression, and epigenetic changes, while mutational signature analysis revealed four distinct clusters.

Two clusters were strongly tied to known risk factors, with smoking-associated SBS4 and alcohol-associated SBS16 signatures dominating. Tobacco-related mutations varied by anatomical site, with laryngeal cancers carrying a higher mutation burden than oral cancers. Two other clusters, enriched with NIRF cases, looked very different.

"They were dominated by endogenous processes, particularly the aging-related SBS1 signature and APOBEC-associated signatures (SBS2 and SBS13) suggesting that internal biological mechanisms, rather than external exposures, play a key role in NIRF OCSCC," said co-author François Virard.

No mutational signatures tied to known environmental carcinogens appeared in the NIRF clusters. NIRF tumors also carried unique driver gene mutations linked to immune function and cell signaling, and gene expression analysis flagged activation of antimicrobial and keratinization pathways. The presence of bacterial components, confirmed histopathologically, points to a possible role for the oral microbiome in tumor development.

Clinically, NIRF tumors showed features of immune evasion, including changes in antigen presentation that could affect responses to checkpoint therapy. APOBEC-driven mutagenesis, meanwhile, suggests possible sensitivity to therapies targeting DNA damage response pathways—opening precision medicine avenues for a patient group whose disease has lacked clear biological explanation.